The overriding theme of the Udall Center at Columbia has been to develop approaches to therapy which prevent progression of disease, and, if also possible, provide lasting restoration of neurologic function. Our efforts have two guiding principals. The first is that development of such therapies ultimately depends on a better understanding of mechanisms of disease. The second is that patients cannot wait for a full understanding of this disease to be in hand before efforts are made to translate new knowledge of mechanisms into treatments. This Project is focused on this second principal. In the current funding period, we have achieved real progress towards this goal by implementing knowledge about the regulation of cell death in the design of two novel gene therapy approaches. One of these approaches utilized dominant negative forms of the mixed lineage kinases to block apoptosis;the other used a constitutively active form of Akt (Myr-Akt). We have identified three limitations of these approaches that we now seek to overcome. First, only the AAV1 Myr-Akt approach protected the axons of the nigrostriatal projection. This feature will be essential for effective future therapies, so it must be refined and developed. Second, our evidence for neuroprotection by Myr-Akt has been obtained only in neurotoxin models;studies must be performed in models with more likely relevance to the human disease. Third, the use Myr-Akt is fraught with many possible undesirable effects, including oncogenesis. Effort must be made to identify downstream pathways that exclusively mediate the desired neuroprotection phenotype. This Project therefore has three Aims intended to address these limitations. In Aim I, we will attempt to validate our observations that Myr-Akt protects not only neuron cell bodies, but also axons. In this Aim, we will also explore whether mTor is a mediator of axon protection, and, if so, whether it does so by suppression of autophagy. In Aim II, we will examine whether the ability of Myr-Akt to protect axons generalizes to a new mouse model that is more likely to be relevant to human PD. We have demonstrated that the principal pathology observed in hl_RRK2(R1441G) BAG transgenic mice is an axonopathy affecting the nigrostriatal projection. In Aim III, we will explore the possibility that the undesired oncogenic phenotype of Akt can be circumvented by the use of a closely-related, but non-oncogenic, kinase, serum and glucocorticoid-induce kinase, hSGK1. Resolution of these limitations will be important steps forward in the development of neuroprotective treatments of PD. RELEVANCE (See instructions): Current therapies for PD treat only its symptoms, not its progression. The goal of our research is to use new knowledge about the mechanisms of neurodegeneration in PD to develop therapies that will block the ongoing neurodegeneration. We have developed one very promising gene therapy approach that uses a protein called Akt, a kinase that protects neurons and their axons from degeneration. The goal of this Project is to improve this approach and to develop promising second-generation alternatives.